tbuckley/cabot-search huggingface dataset:
Proregenerative extracellular matrix hydrogel mitigates pathological alterations of pelvic skeletal muscles after birth injury
Authors: Pamela Duran, Francesca Boscolo Sesillo, Mark Cook, Lindsey Burnett, Shawn A. Menefee, Emmy Do, Saya French, Gisselle Zazueta-Damian, Monika Dzieciatkowska, Anthony J. Saviola, Manali M. Shah, Clyde Sanvictores, Kent G. Osborn, Kirk C. Hansen, Matthew Shtrahman, Karen L. Christman, Marianna Alperin
Journal: Science Translational Medicine (2023)

Pelvic floor disorders, including pelvic organ prolapse and urinary and fecal incontinence, affect millions of women globally and represent a major public health concern. Pelvic floor muscle (PFM) dysfunction has been identified as one of the leading risk factors for the development of these morbid conditions. Childbirth, specifically vaginal delivery, has been recognized as the most important potentially modifiable risk factor for PFM injury; however, the precise mechanisms of PFM dysfunction after parturition remain elusive. In this study, we demonstrated that PFMs exhibit atrophy and fibrosis in parous women with symptomatic pelvic organ prolapse. These pathological alterations were recapitulated in a preclinical rat model of simulated birth injury (SBI). The transcriptional signature of PFMs after injury demonstrated an impairment in muscle anabolism, persistent expression of genes that promote extracellular matrix (ECM) deposition, and a sustained inflammatory response. We also evaluated the administration of acellular injectable skeletal muscle ECM hydrogel for the prevention of these pathological alterations. Treatment of PFMs with the ECM hydrogel either at the time of birth injury or 4 weeks after injury mitigated PFM atrophy and fibrosis. By evaluating gene expression, we demonstrated that these changes are mainly driven by the hydrogel-induced enhancement of endogenous myogenesis, ECM remodeling, and modulation of the immune response. This work furthers our understanding of PFM birth injury and demonstrates proof of concept for future investigations of proregenerative biomaterial approaches for the treatment of injured pelvic soft tissues.
Correlations Between Cardiac Magnetic Resonance and Myocardial Histologic Findings in Fabry Disease
Authors: Raffaello Ditaranto, Ornella Leone, Luigi Lovato, Fabio Niro, Giovanna Cenacchi, Valentina Papa, Chiara Baldovini, Manuela Ferracin, Irene Salamon, Hibba Kurdi, Vanda Parisi, Irene Capelli, Andrea Pession, Rocco Liguori, Luciano Potena, Marco Seri, Sofia Martin Suarez, Nazzareno Galiè, James C. Moon, Elena Biagini
Journal: JACC. Cardiovascular imaging (2023)
Academic hierarchies are an uphill struggle for black women
Authors: Cameron John Sabet, Simar S Bajaj, Fatima Cody Stanford
Journal: BMJ (2023)

The hierarchical, male-dominated environment of academia must change, or it will continue to exclude the contribution and representation of black women, write <b>Cameron John Sabet</b>, <b>Simar Singh Bajaj</b>, and <b>Fatima Cody Stanford</b>
Effects of Prolonged Exposure to Air Pollution and Neighborhood Disadvantage on Self-Rated Health among Adults in the United States: Evidence from the Panel Study of Income Dynamics
Authors: Hannah Lee, Nicole Kravitz-Wirtz, Smitha Rao, Kyle Crowder
Journal: Environmental Health Perspectives (2023)

Background: Although overall air quality has improved in the United States, air pollution remains unevenly distributed across neighborhoods, producing disproportionate environmental burdens for minoritized and socioeconomically disadvantaged residents for whom greater exposure to other structurally rooted neighborhood stressors is also more frequent. These interrelated dynamics and layered vulnerabilities each have well-documented associations with physical and psychological health outcomes; however, much remains unknown about the joint effects of environmental hazards and neighborhood socioeconomic factors on self-reported health status. Objectives: We examined the nexus of air pollution exposure, neighborhood socioeconomic disadvantage, and self-rated health (SRH) among adults in the United States. Methods: This observational study used individual-level data from the Panel Study of Income Dynamics merged with contextual information, including neighborhood socioeconomic and air pollution data at the census tract and census block levels, spanning the period of 1999–2015. We estimated ordinary least squares regression models predicting SRH by 10-y average exposures to fine particulate matter [particles ≤2.5μm in aerodynamic diameter (PM2.5)] and neighborhood socioeconomic disadvantage while controlling for individual-level correlates of health. We also investigated the interaction effects of air pollution and neighborhood socioeconomic disadvantage on SRH. Results: On average, respondents in our sample rated their health as 3.41 on a scale of 1 to 5. Respondents in neighborhoods with higher 10-y average PM2.5 concentrations or socioeconomic disadvantage rated their health more negatively after controlling for covariates [β=−0.024 (95% CI: −0.034, −0.014); β=−0.107 (95% CI: −0.163, −0.052), respectively]. We also found that the deleterious associations of PM2.5 exposure with SRH were weaker in the context of greater neighborhood socioeconomic disadvantage (β=0.007; 95% CI: 0.002, 0.011). Discussion: Study results indicate that the effects of air pollution on SRH may be less salient in socioeconomically disadvantaged neighborhoods compared with more advantaged areas, perhaps owing to the presence of other more proximate structurally rooted health risks and vulnerabilities in disinvested areas (e.g., lack of economic resources, health access, healthy food options). This intersection may further underscore the importance of meaningful involvement and political power building among community stakeholders on issues concerning the nexus of environmental and socioeconomic justice, particularly in structurally marginalized communities. https://doi.org/10.1289/EHP11268
Efficacy of Lorlatinib in Treatment-Naive Patients With ALK-Positive Advanced NSCLC in Relation to EML4::ALK Variant Type and ALK With or Without TP53 Mutations
Authors: Alessandra Bearz, Jean-François Martini, Jacek Jassem, Sang-We Kim, Gee-Chen Chang, Alice T. Shaw, Deborah A. Shepard, Elisa Dall’O’, Anna Polli, Holger Thurm, Gerard Zalcman, Maria Rosario Garcia Campelo, Konstantin Penkov, Hidetoshi Hayashi, Benjamin J. Solomon
Journal: Journal of Thoracic Oncology (2023)

IntroductionLorlatinib, a third-generation ALK tyrosine kinase inhibitor, improved outcomes compared with crizotinib in patients with previously untreated ALK-positive advanced NSCLC in the phase 3 CROWN study. Here, we investigated response correlates using plasma circulating tumor DNA (ctDNA) and tumor tissue profiling.MethodsALK fusions and ALK with or without TP53 mutations were assessed by next-generation sequencing. End points included objective response rate (ORR), duration of response, and progression-free survival (PFS) by blinded independent central review on the basis of EML4::ALK variants and ALK with or without TP53 or other mutation status.ResultsALK fusions were detected in the ctDNA of 62 patients in the lorlatinib arm and 64 patients in the crizotinib arm. ORRs were numerically higher with lorlatinib versus crizotinib for EML4::ALK variant 1 (v1; 80.0% versus 50.0%) and variant 2 (v2; 85.7% versus 50.0%) but were similar between the arms for variant 3 (v3; 72.2% versus 73.9%). Median PFS in the lorlatinib arm was not reached for EML4::ALK v1 and v2 and was 33.3 months for v3; in the crizotinib arm, median PFS was 7.4 months, not reached, and 5.5 months, respectively. ORRs and PFS were improved with lorlatinib versus crizotinib regardless of TP53 mutation status and in patients harboring preexisting bypass pathway resistance alterations. In the lorlatinib arm, PFS was lower in patients who had a co-occurring TP53 mutation. Results from ctDNA analysis were similar to those observed with tumor tissue samples.ConclusionsPatients with untreated ALK-positive advanced NSCLC derived greater clinical benefits, with higher ORRs and potentially longer PFS, when treated with lorlatinib compared with crizotinib, independent of EML4::ALK variant or ALK mutations, TP53 mutations, or bypass resistance alterations.
Hepatic Bile Formation: Developing a New Paradigm
Authors: Norman B. Javitt
Journal: Pharmacological Reviews (2023)

In 1959, Ivar Sperber contrasted bile formation with that of urine and proposed that water flow into the canalicular conduit is in response to an osmotic not a hydrostatic gradient. Early attempts to support the hypothesis using a bile acid, sodium taurocholate, and the hormone secretin to stimulate bile flow led to conflicting data and a moratorium on attempts to further develop the initial proposal. However, current data amplifiy the proposal and indicate both paracellular and transcellular water flow into hepatic ductules and the canalicular conduit in response to an osmotic gradient. Also, the need to further modify the initial proposal became apparent with the recognition that bile acid aggregates (micelles) generate lecithin-cholesterol vesicles that contain water unrelated to an osmotic gradient. As part of this development is the recent introduction of the FLAP technique for direct determination of hepatic duct flow and clarification of the role of biomarkers such as mannitol and polyethylene glycol 900. With the new paradigm these biomarkers may prove useful for quantifying paracellular and transcellular water flow, respectively. <b>Significance Statement</b> It is essential to identify and characterize all the sites for water flow during hepatic bile formation to obtain more precision in evaluating the causes and possible therapeutic approaches to cholestatic syndromes. Updating the Sperber proposal provides a new paradigm that addresses the advances in knowledge that have occurred.
<i>Isocitrate dehydrogenase</i> wt and IDHmut adult-type diffuse gliomas display distinct alterations in ribosome biogenesis and 2’O-methylation of ribosomal RNA
Authors: Hermes Paraqindes, Nour-El-Houda Mourksi, Samantha Ballesta, Jordan Hedjam, Fleur Bourdelais, Tanguy Fenouil, Thiébaud Picart, Frédéric Catez, Théo Combe, Anthony Ferrari, Janice Kielbassa, Emilie Thomas, Laurie Tonon, Alain Viari, Valéry Attignon, Marjorie Carrere, Jessie Perrossier, Stéphane Giraud, Christophe Vanbelle, Mathieu Gabut, Danny Bergeron, Michelle S Scott, Luis Castro Vega, Nathalie Magne, Emmanuelle Huillard, Marc Sanson, David Meyronet, Jean-Jacques Diaz, François Ducray, Virginie Marcel, Sébastien Durand
Journal: Neuro-Oncology (2023)

Abstract Background High-grade adult-type diffuse gliomas (HGGs) constitute a heterogeneous group of aggressive tumors that are mostly incurable. Recent advances highlighting the contribution of ribosomes to cancer development have offered new clinical perspectives. Here, we uncovered that isocitrate dehydrogenase (IDH)wt and IDHmut HGGs display distinct alterations of ribosome biology, in terms of rRNA epitranscriptomics and ribosome biogenesis, which could constitute novel hallmarks that can be exploited for the management of these pathologies. Methods We analyzed (1) the ribosomal RNA 2’O-ribose methylation (rRNA 2’Ome) using RiboMethSeq and in-house developed bioinformatics tools (https://github.com/RibosomeCRCL/ribomethseq-nfandrRMSAnalyzer) on 3 independent cohorts compiling 71 HGGs (IDHwt n = 30, IDHmut n = 41) and 9 non-neoplastic samples, (2) the expression of ribosome biogenesis factors using medium throughput RT-qPCR as a readout of ribosome biogenesis, and (3) the sensitivity of 5 HGG cell lines to RNA Pol I inhibitors (CX5461, BMH-21). Results Unsupervised analysis demonstrated that HGGs could be distinguished based on their rRNA 2’Ome epitranscriptomic profile, with IDHwt glioblastomas displaying the most significant alterations of rRNA 2’Ome at specific sites. In contrast, IDHmut HGGs are largely characterized by an overexpression of ribosome biogenesis factors compared to non-neoplastic tissues or IDHwt glioblastomas. Finally, IDHmut HGG-derived spheroids display higher cytotoxicity to CX5461 than IDHwt glioblastoma, while all HGG spheroids display a similar cytotoxicity to BMH-21. Conclusions In HGGs, IDH mutational status is associated with specific alterations of the ribosome biology and with distinct sensitivities to RNA Pol I inhibitors.
Virus‐Like Nanotherapeutic for Spatiotemporally Enhancing Antigen Presentation and Cross‐Presentation toward Potential Personalized Immunotherapy
Authors: Xiaodi Li, Pengfei Yuan, Haiyuan Yang, Xiaoqing Zong, Caiqi Yang, Xinjie Chen, Yuchao Li, Xiaodie Yan, Yaoqi Wen, Tianci Zhu, Qian Zhang, Wei Xue, Jian Dai
Journal: Advanced Healthcare Materials (2023)

One of the major causes of immunotherapy resistance is the loss of major histocompatibility complex class I (MHC-I) molecules in tumor cells or the downregulation of the class I antigen presentation pathway. In this study, a novel virus-like nanotherapeutic (siRNA@HCM) is developed via encapsulating nanosized siRNA nanoparticles in a hybrid membrane comprising a personalized tumor cell membrane and a universal 293T membrane expressing the mutant vesicular stomatitis virus glycoprotein (mVSV-G). Upon intravenous administration, siRNA@HCM accumulates at the tumor site and provides two potent driving forces for antitumor immunity. First, mVSV-G induces the fusion of siRNA@HCM with tumor cell membranes and directly injects siRNAs into the cytoplasm, significantly improving tumor intrinsic MHC-I antigen presentation. Moreover, mVSV-G can promote the maturation of dendritic cells, thereby achieving highly efficient antigen cross-presentation. The results demonstrate that spatiotemporally enhancing tumor intrinsic antigen presentation and cross-presentation via siRNA@HCM can achieve satisfactory antitumor efficacy and excellent biocompatibility. Immune infiltration analysis shows that siRNA@HCM treatment turns cold tumors into hot tumors. In addition, it significantly promotes the therapeutic effect of programmed death-1 inhibitor. In summary, virus-like nanotherapeutics present a promising approach to enhance the antitumor immune response, with distinct advantages for potential personalized therapy and clinical applications.
The New NCI Precision Medicine Trials
Authors: Lyndsay N. Harris, Charles D. Blanke, Harry P. Erba, James M. Ford, Robert J. Gray, Michael L. LeBlanc, Siwen Hu-Lieskovan, Mark R. Litzow, Selina M. Luger, Funda Meric-Bernstam, Peter J. O'Dwyer, Megan K.D. Othus, Katerina Politi, Lois E. Shepherd, Carmen J. Allegra, Helen X. Chen, S. Percy Ivy, Larissa A. Korde, Richard F. Little, Lisa M. McShane, Jeffrey A. Moscow, David R. Patton, Magdalena Thurin, Laura M. Yee, James H. Doroshow
Journal: Clinical Cancer Research (2023)

Abstract Basket, umbrella, and platform trial designs (master protocols) have emerged over the last decade to study precision medicine approaches in oncology. First-generation trials like NCI-MATCH (Molecular Analysis for Therapy Choice) have proven the principle that studying targeted therapies on a large scale is feasible both from the laboratory and clinical perspectives. However, single-agent targeted therapies have shown limited ability to control metastatic disease, despite careful matching of drug to target. As such, newer approaches employing combinations of targeted therapy, or targeted therapy with standard therapies, need to be considered. The NCI has recently embarked on three second-generation precision medicine trials to address this need: ComboMATCH, iMATCH, and myeloMATCH. The design of these trials and necessary infrastructure are discussed in the following perspective.
Extracellular matrix remodelling in dental pulp tissue of carious human teeth through the prism of single-cell RNA sequencing
Authors: Anamaria Balic, Dilara Perver, Pierfrancesco Pagella, Hubert Rehrauer, Bernd Stadlinger, Andreas E. Moor, Viola Vogel, Thimios A. Mitsiadis
Journal: International Journal of Oral Science (2023)

Abstract Carious lesions are bacteria-caused destructions of the mineralised dental tissues, marked by the simultaneous activation of immune responses and regenerative events within the soft dental pulp tissue. While major molecular players in tooth decay have been uncovered during the past years, a detailed map of the molecular and cellular landscape of the diseased pulp is still missing. In this study we used single-cell RNA sequencing analysis, supplemented with immunostaining, to generate a comprehensive single-cell atlas of the pulp of carious human teeth. Our data demonstrated modifications in the various cell clusters within the pulp of carious teeth, such as immune cells, mesenchymal stem cells (MSC) and fibroblasts, when compared to the pulp of healthy human teeth. Active immune response in the carious pulp tissue is accompanied by specific changes in the fibroblast and MSC clusters. These changes include the upregulation of genes encoding extracellular matrix (ECM) components, including COL1A1 and Fibronectin (FN1) , and the enrichment of the fibroblast cluster with myofibroblasts. The incremental changes in the ECM composition of carious pulp tissues were further confirmed by immunostaining analyses. Assessment of the Fibronectin fibres under mechanical strain conditions showed a significant tension reduction in carious pulp tissues, compared to the healthy ones. The present data demonstrate molecular, cellular and biomechanical alterations in the pulp of human carious teeth, indicative of extensive ECM remodelling, reminiscent of fibrosis observed in other organs. This comprehensive atlas of carious human teeth can facilitate future studies of dental pathologies and enable comparative analyses across diseased organs.
Proteomic and genomic profiling of plasma exosomes from patients with ankylosing spondylitis
Authors: Fataneh Tavasolian, Starlee Lively, Chiara Pastrello, Michael Tang, Melissa Lim, Addison Pacheco, Zoya Qaiyum, Enoch Yau, Zeynep Baskurt, Igor Jurisica, Mohit Kapoor, Robert D Inman
Journal: Annals of the Rheumatic Diseases (2023)

Introduction Recent advances in understanding the biology of ankylosing spondylitis (AS) using innovative genomic and proteomic approaches offer the opportunity to address current challenges in AS diagnosis and management. Altered expression of genes, microRNAs (miRNAs) or proteins may contribute to immune dysregulation and may play a significant role in the onset and persistence of inflammation in AS. The ability of exosomes to transport miRNAs across cells and alter the phenotype of recipient cells has implicated exosomes in perpetuating inflammation in AS. This study reports the first proteomic and miRNA profiling of plasma-derived exosomes in AS using comprehensive computational biology analysis. Methods Plasma samples from patients with AS and healthy controls (HC) were isolated via ultracentrifugation and subjected to extracellular vesicle flow cytometry analysis to characterise exosome surface markers by a multiplex immunocapture assay. Cytokine profiling of plasma-derived exosomes and cell culture supernatants was performed. Next-generation sequencing was used to identify miRNA populations in exosomes enriched from plasma fractions. CD4+ T cells were sorted, and the frequency and proliferation of CD4+ T-cell subsets were analysed after treatment with AS-exosomes using flow cytometry. Results The expression of exosome marker proteins CD63 and CD81 was elevated in the patients with AS compared with HC (q&lt;0.05). Cytokine profiling in plasma-derived AS-exosomes demonstrated downregulation of interleukin (IL)-8 and IL-10 (q&lt;0.05). AS-exosomes cocultured with HC CD4+ T cells induced significant upregulation of IFNα2 and IL-33 (q&lt;0.05). Exosomes from patients with AS inhibited the proliferation of regulatory T cells (Treg), suggesting a mechanism for chronically activated T cells in this disease. Culture of CD4+ T cells from healthy individuals in the presence of AS-exosomes reduced the proliferation of FOXP3+ Treg cells and decreased the frequency of FOXP3+IRF4+ Treg cells. miRNA sequencing identified 24 differentially expressed miRNAs found in circulating exosomes of patients with AS compared with HC; 22 of which were upregulated and 2 were downregulated. Conclusions Individuals with AS have different immunological and genetic profiles, as determined by evaluating the exosomes of these patients. The inhibitory effect of exosomes on Treg in AS suggests a mechanism contributing to chronically activated T cells in this disease.
STING/ACSL4 axis-dependent ferroptosis and inflammation promote hypertension-associated chronic kidney disease
Authors: Li Gao, Junsheng Zhang, Tingting Yang, Ling Jiang, Xueqi Liu, Sheng Wang, Xian Wang, Yuebo Huang, Huaying Wang, Mengya Zhang, Tingting Gong, Lijuan Ma, Chao Li, Chaoyong He, Xiao-ming Meng, Yonggui Wu
Journal: Molecular Therapy (2023)

Hypertension is a primary modifiable risk factor for cardiovascular diseases, which often induces renal end-organ damage and complicates chronic kidney disease (CKD). In the present study, histological analysis of human kidney samples revealed that hypertension induced mtDNA leakage and promoted the expression of stimulator of interferon genes (STING) in renal epithelial cells. We used angiotensin II (AngII)- and 2K1C-treated mouse kidneys to elucidate the underlying mechanisms. Abnormal renal mtDNA packing caused by AngII promoted STING-dependent production of inflammatory cytokines, macrophage infiltration, and a fibrogenic response. STING knockout significantly decreased nuclear factor-κB activation and immune cell infiltration, attenuating tubule atrophy and extracellular matrix accumulation in vivo and in vitro. These effects delayed CKD progression. Immunoprecipitation assays and liquid chromatography-tandem mass spectrometry showed that STING and ACSL4 were directly combined at the D53 and K412 amino acids of ACSL4. Furthermore, STING induced renal inflammatory response and fibrosis through ACSL4-dependent ferroptosis. Last, inhibition of ACSL4 using small interfering RNA, rosiglitazone, or Fer-1 downregulated AngII-induced mtDNA-STING-dependent renal inflammation. These results suggest that targeting the STING/ACSL4 axis might represent a potential strategy for treating hypertension-associated CKD.
Manganese‐Based Redox Homeostasis Disruptor for Inducing Intense Ferroptosis/Apoptosis Through xCT Inhibition And Oxidative Stress Injury
Authors: Qi Dong, Jie Wang, Jiahui Liu, Lei Zhang, Zhigang Xu, Yuejun Kang, Peng Xue
Journal: Advanced Healthcare Materials (2023)

Intracellular redox homeostasis plays an important role in promoting tumor progression, development and even treatment resistance. To this end, redox balance impairment may become a prospective therapeutic target of cancer. Herein, a manganese-based homeostasis modulator (MHS) is developed for inducing severe reactive oxygen species accumulation and glutathione (GSH) deprivation, where such redox dyshomeostasis brings about dramatic ferroptosis/apoptosis. Tumor-specific degradation of manganese oxide nanocarriers contributes to hypoxia alleviation and loaded cargo release, resulting in apoptosis by augmented sonodynamic therapy and chemodynamic therapy. On the other hand, regional oxygenation significantly downregulates the expression of activating transcription factor 4, which can synergize with the released sulfasalazine to inhibit the downstream cystine antiporter xCT. Biosynthesis of GSH is sufficiently interrupted by the xCT suppression, leading to the reduction of glutathione peroxidase 4 (GPx4) level. The resultant excessive lipid peroxides promote intense ferroptosis to motivate cell death. On this basis, splendid treatment outcome by MHS is substantiated both in vitro and in vivo, thanks to the synergy of antitumor immunity elicitation. Taken together, this paradigm provides an insightful strategy to evoke drastic ferroptosis/apoptosis toward therapeutics and may also expand the eligibility of manganese-derived nanoagents for medical applications.